Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types. ### Competing Interest Statement The authors have declared no competing interest. Data generated in this study has been deposited in the GEO database under accession “GSE254242”. The publicly available data was accessed as follows: GP5d ChIP-seq data for H3K27ac (“GSM5454417”), H3K27me3 (“GSM5454428”), and p53 (“GSM5454412”) were acquired from GEO database under accession “GSE180158”. GP5d ATAC-seq (“GSE221051”), ChIP- seq for H3K4me3 ("GSM6841187”), rabbit IgG ("GSM6841190”) and mouse IgG ("GSM6841189”), and RNA-seq for DMSO treated (“GSM6841203”, “GSM6841204”, “GSM6841205”) and DNMTi-HDACi treated GP5d cells (“GSM6841206”, “GSM6841207”, “GSM6841208”) was acquired from GEO database under accession “GSE221053”. GP5d H3K4me1 (“GSM1240814”) was obtained with the GEO accession “GSE51234”. OE19 ATAC- seq (“ERR1698333”) was downloaded with accession code ERX1767841. OE19 KAS-seq (“ERR8135308”) was acquired from accession code “E-MTAB-11356”. OE19 CUT&TAG data for H3K27me3 (ERR8105268), H3K4me1 (ERR8105270), RNA PolII (ERR8105275) and RNA PolIISp5 (ERR8105277) was obtained from ENA accession “E-MTAB-11356”. A375 RNA-seq (“GSM5320279”, “GSM5320280”, “GSM5320281”) and A375 SETDB1-KO RNA-seq (“GSM5320275”, “GSM5320276”, “GSM5320277”) was acquired from GEO accession “GSE155972”.